Protein C Deficiency

Congenital or acquired control of the clotting mechanism resulting in a widespread thrombotic tendency. Protein C is a vitamin K-dependent serine protease zymogen that selectively inhibits factors Va and VIII:C in human plasma, and thus has an important anticoagulant role. It is associated with an increased tendency to thrombosis. It is either inherited or acquired: bacterial sepsis (especially of meningococcal origin), hepatic disease, disseminated intravascular coagulation, l-asparaginase therapy, nephrotic syndrome, conditioning therapy in bone marrow transplantation, warfarin-induced skin lesions.

Congenital Thrombotic Protein C Deficiency; Hereditary Thrombophilia; PC Deficiency; ProC Deficiency.

The addition of Protein C deficiency in the list of thrombotic diseases was suggested by J.H. Griffin in 1981.

Inherited forms: 1:200 to 1:300 for heterozygotes; 1:200,000 for homozygotes.

Autosomal dominant trait with variable expressivity. Gene map locus: 2q13-q14.

Inherited thrombophilia has been associated with abnormalities of antithrombin III, fibrinogen, and plasminogen. Protein C is a vitamin K-dependent serine protease anticoagulant factor. It has several roles: (a) it is converted on site and on demand during the coagulation activation into activated protein C; its anticoagulant activity is related to inactivation of factors Va and VIIIa; the presence of protein S as a nonenzymatic cofactor is necessary for those reactions; (b) it promotes fibrinolysis by binding plasminogen activator inhibitor I; (c) it prevents the proinflammatory consequences of local thrombin formation, for example, release of vasoactive proinflammatory factors (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, etc.), and an increase of endothelial permeability. Consequently, a deficiency in protein C results in defective control of the clotting mechanism with a widespread thrombotic tendency. Heterozygotes show an increased thrombotic tendency, whereas homozygotes present with severe thrombotic sequelae in the neonatal period. Most cases of protein C deficiency have had a quantitative defect in the protein C molecule. Protein C deficiency with a mutation that causes diminished synthesis of protein has been referred to as type I and that with synthesis of a dysfunctional molecule as type II.

Positive family history and a significant history of thrombosis or gangrene (skin, retinal, etc.). Severe symptoms typically develop when the serum protein C level is below 20 to 25% of normal (4 μg/mL). Specific laboratory tests and assays are needed to exclude other causes of disseminated intravascular coagulation.

Heterozygotes for Protein C Deficiency (serum concentrations 40 to 60% of normal) usually presents in adolescence with recurrent thrombophlebitis, deep venous thrombosis, and pulmonary thromboembolism. There is also an increased risk of thrombotic renal and cerebral disease and an increased risk of myocardial infarction.

Homozygotes manifest fatal thromboses in the neonatal period—massive subcutaneous thrombosis (neonatal purpura fulminans) with cutaneous necrosis, gangrene, and widespread venous thrombosis, which usually starts in the first 24 hours of life. Severe bilateral vitreous hemorrhages, gangrene, and widespread venous thrombosis have been reported. Bilateral adrenal hemorrhage may lead to abdominal pain, hypotension, and hyponatremia. Hypertension and congestive cardiac failure commonly result from renal involvement. Treatment with heparin, antiplatelet drugs, or both is not effective. The only successful treatment is protein C replacement using protein C human concentrate, fresh-frozen plasma, or factor IX concentrate.

In case of portal hypertension with normal or near-normal liver function (e.g., in case of portal cavernoma), reestablishing portal flow through the liver restores normal serum protein C levels. Availability of a human protein C concentrate purified by monoclonal antibody allows specific replacement of protein C; the initial dose is 60 to 80 IU/kg.

Protein C Deficiency does not cause abnormalities in the routine screening coagulation tests; a high index of suspicion is necessary in case of familial or personal history of thrombotic events at a young age, and in patients at risk for acquired protein S deficiency (e.g., nephrotic syndrome, asparaginase therapy). Detailed systemic review, particularly of the cardiovascular and renal systems, and the CNS. Optimize antihypertensive therapy and continue all medications until the day of surgery. Investigations: CBC, urea and creatinine, serum electrolytes, coagulation studies, ECG. Fresh-frozen plasma and/or protein C human concentrate should be available to manage the hypercoagulability state in such patients. Adrenal hormone supplementation may be required. Hypertension may also require specific management. Ensure adequate protein C levels by human protein C concentrate, or fresh-frozen plasma administration.

Thrombosis may be triggered by endothelial damage, immobility, and blood stasis—all common occurrences during surgery and anesthesia. Some authors advocate avoidance of endotracheal intubation because airway trauma may result in oral and tracheal submucosal thrombosis and necrosis. Regional anesthesia should be considered as an alternative to general anesthesia. Pad pressure and bony points adequately to avoid pressure necrosis. Hypovolemia and hypotension should be avoided. Antiembolism stockings and subcutaneous low-molecular-weight heparin therapy might be appropriate.

Care should be taken with drugs that are excreted via the kidneys especially if there is impairment of renal function.